Hollow granular medicine and its preparation

ABSTRACT

A granular medicine with slow drug-release characteristics that is sufficiently absorbed in the intestines, in which the granular medicine has a hollow spherical structure, a drug is dispersed in the shell, which mainly consists of an enteron-soluble polymer. The method for preparing the medicine includes the steps of: (a) mixing a hydrophilic or hydrophobic drug with an enteron-soluble polymer in a mixture of an aliphatic alcohol and a chlorohydrocarbon; and (b) pouring this mixture into water or an aqueous medium, and stirring the solution to precipitate the medicine.

This is a division of application Ser. No. 07/367,948, filed June 19,1989.

BACKGROUND OF THE INVENTION

This invention relates to a hollow granular medicine and itspreparation, and more particularly, but not exclusively, to a granularmedicine having a spherical structure and slow drug-releasecharacteristics.

Oral drugs, which are promptly absorbed in the alimentary canal and arealso rapidly lost from the blood, are generally film-coated ormicrocapsulated to cause the slow drug-release. These techniques,however, only delay the drug release and hence have a problem: while adrug can only be absorbed in the upper portion of small intestines, thedrug might be released from a capsule or a pill after passing theabsorption site. Even if slow drug release is attained, the drug that isreleased after passing the absorption site is not utilized, thuslowering the efficacy of the drug.

A drug whose solubility varies with pH generally differs betweenindividuals in the incidence and duration of the effect. When the drugis treated to cause the slow drug release, it differs even more.Examples of such drugs include ibuprofen, ketoprofen and tranilast.

SUMMARY OF THE INVENTION

The objective of the invention is to provide a medicine with slowdrug-release characteristics that produces fewer differences betweenindividuals in effect and that has high utilization-efficiency, and alsoto provide a simple method of preparation of the drug.

The above and other related objectives are realized by a hollow granularmedicine with a spherical structure, in which a drug is distributed inthe shell mainly consisting of an enteron-soluble polymer.

A method for preparing this hollow granular medicine with a sphericalstructure, includes the steps of: (a) mixing a drug with anenteron-soluble polymer in a mixture of an aliphatic alcohol and achlorohydrocarbon; and (b) pouring the resulting mixture into water oran aqueous medium, and stirring the solution to precipitate themedicine.

DESCRIPTION OF PREFERRED EMBODIMENT

A hydrophilic drug may be used in this invention but a hydrophobic oneis generally preferable. Examples of such drugs include ibuprofen,ketoprofen, tranilast, 5-fluorouracil, tolbutamide, and indometacin.

A granular medicine of this invention has a spherical structure in whicha drug is homogeneously distributed only in the shell, which mainlyconsists of an enteron-soluble polymer. The medicine has a coating of anenteron-soluble polymer that is insoluble in saliva and hence does notstimulate the tip of a tongue during administration. Since the medicineis hollow and its specific gravity is small, it floats in the stomachfor a long while before being transported to an absorption site; so, themedicine possesses slow drug release characteristics. After beingtransported to the intestines, the medicine rapidly releases the drugcomponent with the rise in pH, thus permitting the efficient absorptionof the drug component.

The diameter of the granular medicine of the invention is 10 to 2,000 μmand thickness of the shell thereof is 1 to 200 μm.

The enteron-soluble polymer used may be an acrylic polymer or acellulose polymer. The examples of the cellulose polymer includehydroxypropylmethylcellulose phthalate, hydroxypropylmethylcelluloseacetate succinate, cellulose acetate phthalate, andcarboxymethylethylcellulose. The acrylic polymer can be anyenteron-soluble film-coating agent, for example, a copolymer of acrylateor methacrylate as shown in structural formulas I or II, ##STR1## inwhich the molar ratio of acid to ester is preferably 1 to 1 to 1 to 2.This copolymer may be partially denaturated or copolymerized with asmall amount of another monomer: for example, a quaternary ammoniumgroup-containing copolymer as shown in formula III; ##STR2## in which:R¹ is --H, or --CH₃ ; and

R² is --CH₃, or --C₂ H₅.

The molecular weight of the polymer used in this invention is generally135,000 to 200,000.

To prepare this granular medicine, a powdery hydrophobic drug is mixedwith an enteron-soluble polymer in a mixture of an aliphatic alcohol anda chlorohydrocarbon to prepare the mixed solution or suspension. Theamount of the enteron-soluble polymer used may be 20 to 1,000 wt % withrespect to the drug component, but 50 to 400 wt % is preferable. If theamount of the polymer is too large or too small, the object of theinvention, hollow granular medicine, is not efficiently obtained.

The aliphatic alcohol used is a lower one containing one to four carbonatoms (e.g., methanol, ethanol, 2-propanol, and butanol). Thechlorohydrocarbon used is an aliphatic one (e.g., methylene chloride,chloroform, ethylene chloride, and chloroethane). The amount of thechlorohydrocarbon used with respect to the aliphatic alcohol may be 0.5to 2 times in volume, but 0.8 to 1.2 times in volume preferable. Thetotal amount of both should be adjusted so that the drug concentrationof the mixture becomes 0.1 to 20 wt %, preferably 0.5 to 10 wt %. Thedrug component may be mixed with the enteron-soluble polymer, thealiphatic alcohol, and the chlorohydrocarbon using any method. Themixing can be performed at room temperature. In this invention, thepolymer solution above may include an organic solvent containing ahydroxyl group or a molten vehicle like wax to improve the plasticity ofthe polymer film and thus to obtain hollow granules with better shapes.The organic solvent may be, for example, propylene glycol, glycerine, orethylene glycol. The vehicle may be, for example, monostearin,tristearin, stearic acid, cetyl alcohol, or stearyl alcohol. The amountof these agents used should be 1 to 100 wt % with respect to theenteron-soluble polymer.

The various homogeneously mixed components including the drug component,are then poured into water and are stirred, thus allowing the drugcomponent to disperse and then allowing the hollow granules toprecipitate. The amount of water used is 300 wt % or more, but 1,000 wt% or more is preferable. If the amount of water used is too small,cohesion of the particles of the components occurs during stirring, sohigh-quality hollow granules will not form.

This drug mixture may be mixed with water prior to stirring, or may bepoured into the water while it is being stirred. The latter method ispreferable because the drug component can homogeneously disperse andhollow granules with a better quality can be obtained. The stirring iscarried out at a temperature of 20° to 60° C. for 5 through 300 minutes;preferably 30 through 150 minutes. The solution is stirred by apropeller-type agitator or a magnetic stirrer at 200 to 1,000 r.p.m.

Using a surfactant or a water-soluble polymer in the water is preferablesince it improve granulation efficiency to produce better-quality hollowgranular medicine. The surfactant may be anionic (e.g., sodiumlaurylsulfate, sodium benzenesulfonate, sodium laurylbenzensulfonate orsodium oleate), or it may be cationic (e.g., cetyltrimethylammoniumbromide), or it may be nonionic (e.g., a polyoxyethylene sorbitan fattyacid ester, a monoester or triester of oleic acid, or a sorbitan fattyacid ester). The water-soluble polymer may be polyvinyl alcohol,polyethylene glycol, methylcellulose, or hydroxypropylcellulose.

The amount of the surfactant or the water-soluble polymer used is 1 to300 wt % with respect to the drug component. If the amount used is toosmall, the effect of the additives is insufficient; but too large anamount is uneconomical since the effect levels off.

In this manner, a granular medicine with a spherical structureprecipitates from the medium, in which the drug component ishomogeneously dispersed in the shell, which mainly consists of anenteron-soluble polymer. The medicine has a film of the enteron-solublepolymer, and has a hollow that gives the medicine a low specificgravity. The size of granules deposited is normally 10 to 2,000 μm.

The hollow granules are then recovered from the mixture by solid-liquidseparation, are washed with water, and are dried to remove the aliphaticalcohol and the chlorohydrocarbon used as the solvent. The granularmedicine can be dried either chemically or physically (e.g., by warming,reducing pressure, or using a desiccant such as silica gel).

The drug component does not deteriorate in the process of the invention,thus maintaining its efficiency and safety unchanged.

Some examples of the invention are described now. Since there may bemany modifications without departing from the scope of the invention,the examples below are not intended to limit the invention to theexamples, but are intended to illustrate the invention more clearly.

EXAMPLE 1

1.5 g of powdery ibuprofen and 2.0 g of an enteron-soluble acrylicpolymer are added to 10 ml of ethanol and 10 ml of dichloromethane in a50 ml glass vessel, and are stirred by a magnetic stirrer for 60 minutesat room temperature so they are homogeneously mixed. The enteron-solubleacrylic polymer used is a copolymer of methacrylic acid and methylmethacrylate with a molecular weight of 135,000 (Rohn Pharma trademark"EUDRAGIT S" or "EUDRAGIT L").

While 200 ml of water including 0.025 wt % sodium laurylbenzenesulfonateis being stirred in a 500 ml glass vessel with a stirring wing at 300r.p.m. at 40° C., the drug mixture is dropped into the water. Theresulting solution is stirred for 60 minutes to deposit granules withthe spherical hollow structure. The resulting deposit is filtered,washed with water, and then dried by the blowing air at 40° C. torecover the hollow granular ibuprofen of the present invention.

The size of the hollow granules obtained in our experiment was 630 μm onaverage and the yield was 90%. In oral administration, ibuprofen of thegranular medicine does not stimulate the tip of a tongue, and does notprematurely deteriorate either. An elution test shows that the granuledibuprofen of the sample has better d rug release characteristics thanoriginal ibuprofen powders: the original drug ibuprofen, is released ata constant speed.

The medicine obtained has a spherical structure in which noncrystallineibuprofen is distributed in the shell, which mainly consists of theenteron-soluble polymer The hollow granules of the sample float on waterfor four to five hours.

EXAMPLE 2

0.5 g of powdery tranilast and 1.0 g of an enteron-soluble acrylicpolymer are added to 5 ml of ethanol and 5 ml of dichloromethane in a 50ml glass vessel, and are stirred by a magnetic stirrer for 60 minutes atroom temperature so they are homogeneously mixed. The enteron-solubleacrylic polymer used is a copolymer of methacrylic acid and methylmethacrylate with molecular weight of 135,000 (Rohm Pharma trademark"EUDRAGIT S").

While 200 ml of water including 0.5 wt % polyvinyl alcohol is beingstirred in a 500 ml glass vessel with a stirring wing at 300 r.p.m. at40° C., the drug mixture is dropped into the water. The resultingsolution is stirred for 60 minutes to deposit granules with a sphericalhollow structure. The resulting deposit is filtered, washed with water,and then dried by blowing air at 40° C. to recover the hollow granulartranilast of the present invention.

The size of the hollow granules obtained in our experiment was 410 μm onaverage and the yield was 80%. An elution test shows that the granuledtranilast of the sample has better drug release characteristics thanoriginal tranilast powders. The granuled tranilast does not deteriorateat all.

The medicine obtained has a spherical structure, in which tranilast isdistributed in the shell, which mainly consists of the enteron-solublepolymer.

EXAMPLE 3

0.5 g of powdery 5-fluorouracil and 1.0 g of an enteron-soluble acrylicpolymer are added to 5 ml of methanol, 5 ml of dichloromethane, and 0.01g of propylene glycol in a 25 ml glass tube, and are shaked by ahorizontal shaker for 60 minutes at room temperature so they arehomogeneously mixed. The enteron-soluble acrylic polymer used is acopolymer of methacrylic acid and methyl methacrylate with molecularweight of 135,000 (Rohm Pharm trademarks "EUDRAGIT S" or "EUDRAGIT L").

While 200 ml of water including 0.5 wt % polyvinyl alcohol is beingstirred in a 500 ml glass vessel with a stirring wing at 300 r.p.m. at40° C., the drug mixture is dropped into the water. The resultingsolution is stirred for 60 minutes to deposit granules with a sphericalhollow structure. The resulting deposit is filtered, washed with water,and then vacuum dried for 24 hours to recover the hollow granular5-fluorouracil of the present invention.

The size of the hollow granules obtained in our experiment was 500 μm onaverage and the yield was 75%. The granuled 5-fluorouracil does notdeteriorate at all.

The medicine obtained has a spherical hollow structure, in which5-fluorouracil is dispersed in the shell, which mainly consists of theenteron-soluble polymer.

We claim:
 1. A method for preparing a hollow granular medicine with aspherical hollow structure, in which a drug is distributed in the shellof the structure that essentially consists of an enteric polymer,including the steps of:(a) mixing a drug with an enteric polymer in amixture of an aliphatic alcohol and a chlorohydrocarbon, where theamount of the enteric polymer is from 20 to 1000% by weight with respectto the drug component; (b) pouring the resulting solution into anaqueous medium and stirring the solution to make the hollow granularmedicine with the spherical hollow structure; (c) separating the hollowgranular medicine from the solution; (d) rinsing the hollow granularmedicine with water; and (e) drying the hollow granular medicine.
 2. Amethod as claimed in claim 1, in which the drug is hydrophobic.
 3. Amethod as claimed in claim 1, in which the aliphatic alcohol is a loweraliphatic alcohol containing one to four carbon atoms.
 4. A method asclaimed in claim 1, in which the chlorohydrocarbon is aliphatic.
 5. Amethod as claimed in claim 1, in which a surfactant is added into theaqueous medium prior to stirring in step (b).
 6. A method as claimed inclaim 1, in which a water-soluble polymer is added into the aqueousmedium in step (b).
 7. A method as claimed in claim 1, in which anorganic solvent having a hydroxyl group is added to the solution of thealiphatic alcohol and the chlorohydrocarbon in step (a).
 8. A method asclaimed in claim 1, in which an organic solvent including a wax moltenvehicle is added to the solution of the aliphatic alcohol and thechlorohydrocarbon in step (a).
 9. A method as claimed in claim 1, inwhich the drug is selected rom the group consisting of ibuprofen,ketoprofen, tranilast, 5-fluorouracil, tolbutamide, and indometacin. 10.A method as claimed in claim 1, in which the granular medicine is solidand the diameter of the medicine ranges from 10 to 2,000 μm and thethickness of the shell thereof is from 1 to 200 μm.
 11. A method asclaimed in claim 1, in which the enteric polymer is selected from thegroup consisting of an acrylic polymer and a cellulose polymer.
 12. Amethod as claimed in claim 11, in which the cellulose polymer isselected from the group consisting of hydroxypropylmethylcellulosephthalate, hydroxyproplymethylcellulose acetate succinate, celluloseacetate phthalate, and carboxymethylethylcellulose.
 13. A method asclaimed in claim 11, in which the acrylic polymer is an entericfilm-coating agent consisting of a copolymer of methacrylic ester.
 14. Amethod as claimed in claim 13, in which the copolymer of methacrylicester has a molar ratio of acid to ester of from 1:1 to 1:2.
 15. Amethod as claimed in claim 11, in which the copolymer is partiallydenaturated or copolymerized with a small amount of another monomer of aquaternary ammonium group-containing copolymer.
 16. A method as claimedin claim 11, in which the molecular weight of the polymer is from135,000 to 200,000.
 17. A method as claimed in claim 6, in which theamount of the water-soluble polymer is from 1 to 300% by weight withrespect to the drug component.
 18. A method as claimed in claim 1, inwhich the chlorohydrocarbon is selected from the group consisting ofmethylene chloride, chloroform, ethylene chloride, and chloroethane. 19.A method as claimed in claim 1, in which the amount of thechlorohydrocarbon with respect to the aliphatic alcohol is 0.5 to 2times in volume.
 20. A method as claimed in claim 1, in which the amountof the chlorohydrocarbon with respect to the aliphatic alcohol is 0.8 to1.2 times in volume.
 21. A method as claimed in claim 1, in which thetotal amount of the aliphatic alcohol and the chlorohydrocarbon isadjusted such that the drug concentration with respect to the resultingsolution is 0.1 to 20% by weight.
 22. A method as claimed in claim 8, inwhich the total amount of the aliphatic alcohol and thechlorohydrocarbon is adjusted such that the drug concentration withrespect to the resulting solution is 0.5 to 10% by weight.
 23. A methodas claimed in claim 7, in which the organic solvent is selected from thegroup consisting of propylene glycol, glycerine, and ethylene glycol.24. A method as claimed in claim 8, in which the molten vehicle isselected from the group consisting of monostrearin, tristearin, stearicacid, cetyl alcohol, and stearyl alcohol.
 25. A method as claimed inclaim 23, in which the amount of the organic solvent is from 1 to 100%by weight with respect to the enteric polymer.
 26. A method as claimedin claim 24, in which the amount of the molten vehicle is from 1 to 100%by weight with respect to the enteric polymer.
 27. A method as claimedin claim 1, in which the aqueous medium in step (b) is water, and theamount of water is 300% or more by weight with respect to the resultingsolution.
 28. A method as claimed in claim 27, in which the amount ofwater is 1000% or more by weight.
 29. A method as claimed in claim 1, inwhich the resulting solution is mixed with the aqueous medium duringstirring.
 30. A method as claimed in claim 1, in which the solution ispoured into the aqueous medium when the aqueous medium is being stirredto make the drug homogeneously disperse and form hollow granules.
 31. Amethod as claimed in claim 1, in which the stirring is carried out at atemperature of between 20° and 60° C. for 5 to 300 minutes.
 32. A methodas claimed in claim 1, in which the resulting solution is stirred by apropeller agitator or a magnetic stirrer at 200 to 1,000 r.p.m.
 33. Amethod as claimed in claim 5, in which the surfactant is an anionicsurfactant.
 34. A method as claimed in claim 5, in which the surfactantis a nonionic surfactant.
 35. A method as claimed in claim 33, in whichthe surfactant is selected from the group consisting of sodiumlaurylsulfate, sodium benzenesulfonate, sodium laurylbenzenesulfonate,and sodium oleate.
 36. A method as claimed in claim 34, in which thesurfactant is selected from the group consisting of a polyoxyethylenesorbitan fatty acid ester, a monoester or triester of oleic acid, and asorbitan fatty acid ester.
 37. A method as claimed in claim 6, in whichthe water-soluble polymer is selected from the group consisting ofpolyvinyl alcohol, polyethylene glycol, methylcellulose, andhydroxyproplycellulose.
 38. A method as claimed in claim 5, in which theamount of the surfactant is from 1 to 300% by weight with respect to thedrug component.
 39. A method as claimed in claim 1, wherein the amountof the enteric polymer is from 50 to 400% by weight with respect to thedrug component.